Steroid alpha-halo ketals



Patented May 7, 1957 STEROID a-HALO KETALS Barney J. Magerlein and AVern McIntosh, In, Kalamazoo, and Robert H. Levin, Kalamazoo Township,Kalamazoo County, Micln, assignors to The Upjohn Company, Kalamazoo,Mich., a corporation of Michigen No Drawing. Application December 6,1955, Serial No. 551,238

9 Claims. (Cl. 260-23955) This invention relates to certain sterioda-halo ketals and more particularly to novel S-ketals of4-halo-17a,2ldihydroxypregnane-3,2l-diones which contain an oxygensubstituent in the ll-position, and 21-acylates thereof. The compoundsof the invention may be represented by wherein X is a halogen of atomicweight from 35 to 80, i. e., chlorine or bromine, and wherein R isselected from the group consisting of hydrogen and loweralkyl groupssuch as, for example, methyl, ethyl, propyl, isopropyl, butyl,l-methylpropyl, amyl, hexyl, and the like, n is an integer from one totwo, inclusive, and R is hydroxy or an acyloxy group, the acyl radicalof which is that of a hydrocarbon monocarboxylic acid, preferablycontaining from one to eight carbon atoms, inclusive, such as acetoxy,propionoyloxy, butyroyloxy, valeroyloxy, hexanoyloxy, heptanoyloxy,octanoyloxy, benzoyloxy, and others, and R" is an oxygen substituent, e.g., aor fi-hydroxy or keto.

The compounds of this invention find use as intermediates in thepreparation of known pharmaceutically active compounds such as cortisoneand hydrocortisone and 21- acylates thereof. For example, Kendallscompound F acetate is prepared from a4-halo-1lp,l7a-dihydroxy-2lacetxyprcgnane-3,20-dione 3-monoketal bytreatment with 2,4-dinitrophenylhydrazine in the presence of sulfuricacid, which results in the formation of the 3-(2,4-dinitrophenylhydrazone) and the elimination of hydrogen halide to form adouble bond between carbon atoms four and five and give11,9,1?m-dihydroxy-Zl-acetoxy-4- pregnene 3,20 dione 3 (2,4dinitrophenylhydrazone). Removal of the hydrazone group with pyruvicacid gives Kendalls compound F acetate. Likewise, free Kendalls compoundF is prepared from a 4-halo-11fl,17a,21-trihydroxypregnane-3,ZO-dione3-monoketal by treatment with 2,4-dinitrophenylhydrazine in the presenceof sulfuric acid followed by removal of the hydrazone group with pyruvicacid.

The compounds of the present invention can be made by reacting 4-halo17oz -hydroxy 21 acyloxypregnane- 3 ,1 1,20-triones,4-halo-1l(1,17a-dihydroxy-2l-acyloxypreg mane-3,20-diones or 4-halo-l1,8,l7a-dihydroxy-2l-acyloxypregnane-3,20-diones in which the 21-acylradical is that of a hydrocarbon monocarboxylic acid containing from oneto eight carbon atoms, inclusive, with an alkyleue glycol, preferably analkane-l,2-diol or an alkane-1,3-diol such as, for example, ethyleneglycol, propane-1,2-diol, propane-1,3-diol, butane-1,2-diol,pentane-l,2-diol, 3- methylpentane-l,2-diol, hexane-1,3-diol,octane-1,2-diol and the like in the presence of an acid catalyst,preferably a mineral acid or an organic sulfonic acid. Representativecatalysts are the metaand para-toluenesulfonic acids, napthalenesulfonicacid, benzenesulfonic acid, orthochlorobenzenesulfonic acid,hydrochloric acid, and sulfuric acid, with para-toluenesulfonic acidbeing the preferred acid catalyst. The ketalizing reaction can beconducted in any organic solvent with which the reactants and productsare non-reactive such as, for example, benzene, toluene, xylene,methylene chloride, petroleum ether, ether, or the like. However, thepreferred solvents are those which form an azeotrope with water andafiord a means of removing the water as it is formed in the course ofthe reaction. For this reason the reaction is usually conducted at thereflux temperature of the mixture, such temperature depending, ofcourse, upon the solvent and the particular reaction conditions, e. g.,pressure, employed.

The ketalizing reaction is carried out at a temperature below about 200degrees centigrade, preferably under reflux conditions, to causeconversion of the 3-ketone group to a ketal group. In carrying out thereaction the 4-halo-17u-hydroxy 21 acyloxypregnane-3,20-dione containingan oxygen substituent in the ll-position is mixed with at least thetheoretical amount of the alkane- 1,2-diol or alkane-l,3-dio1 in anorganic solvent at a temperature between about twenty and about 200degrees centigrade, preferably between about twenty and about degreescentigrade. Ordinarily, it is preferred to use an excess of thealkanediol, preferably between about two and about 25 moles per mole ofthe steroid. The time required for the reaction is not critical and maybe varied between about one and about 24 hours, the length of time beingsomewhat dependent upon the temperature, the ketalizing reagent and thecatalyst employed, as will be apparent to one skilled in the art.

The foregoing reaction provides for the preparation of4-halo-l7a-hydroxy-ll-oxygen-substituted-2l-acyloxy- 3,20-dione3-monoketals. The corresponding free 2l-hydroxy compound, i. e., the4-halo-17a,2l-dihydroxy-l1- oxygen-substituted-pregnane-3,20-dione canbe prepared by hydrolysis under mild hydrolyzing conditions as forexample, with dilute alkali at approximately room tempcrature.

The novel compounds of this invention can also be prepared in accordancewith the method disclosed in application Serial No. 304,852, filedAugust 16, 1952, of which this application is a continuation-in-part.According to the disclosure of that application, a4-halo-ll,8,l7adihydroxypregnane-3,20-dione 3,20-diketal, a4-halolla,17a-dihydroxypregnane-3,20-dione 3,20-diketal or a4-halo-l7a-hydr0xypregnane-3J1,20-trione 3,20-diketal is selectivelyhydrolyzed with an acid hydrolyzing agent to produce the corresponding3-monoketal. These monoketals thus produced are then reacted withbromine to produce the corresponding 2l-bromo monoketals, as forexample, 4-halo 21 bromo-1 1,3,l7a-dihydroxypregnane- 3,20dione3-mon0ketal or 4-halo-2l-bromo-17a-hydroxypregnane-3,l1,20-trione3-monoketal. The 2l-bromo-3- monoketals are then reacted with analkali-metal salt of a hydrocarbon monocarboxylic acid containing fromone to eight carbon atoms, inclusive, together with an alkalimetaliodide, preferably in the presence of the free acid corresponding to thealkali-metal salt to produce the 4halo-1l-oxygen-substituted-l7a-hydroxy 21 acyloxy pregnane-3,20-dione3-monoketal, the acyl group corresponding to that of the alkali-metalsalt.

The alternative methods of preparation of the compounds of thisinvention, i. e., the direct ketalization of the 3,20-dione compoundpossessing a Zl-acyloxy group and the selective hydrolysis of the3,20-diketal in which the 2l-carbon is unsubstituted followed bybromination and introduction of the acyloxy group each have separateadvantages. For example, the latter method permits the use of anoriginal starting material which is in cornparatively more abundantsupply, i. e., 3a,l'7adihydroxypregnane-ll,20-dione isarett, J. Am.Chem. Soc, 70 1454 (1948)]. It also has the advantage of embracing anoverall process in which the ll-kcto group can be transformed to the11;9hydroxy group while the 3 and the ZO-keto groups are protected byk'et-aiization.

The starting 4-halo-3.20-diketal compounds are prepared by reacting a4-halo-3,20dik'etorre such as A chimel7a-hydroxypregnane-3 LZO-trione=or 4-ch'loro-l 1 3,171:- dihydroxypregnane-3,20-dione with analkanediol as previously described in connection with themonoice'talization of a 4-chloro-2l-acyloxy-3,20-dione, usitig "insteadpreferably five to about fifty moles of alkanediol per mole of steroid.The ketalizi-ng reaction can be conducted in any organic solvent withwhich the reactants and products are non-reactive as previouslydescribed.

Reduction of the ll-keto group of the 4-haio Wu'- hydroxy-pregnane-3,l1,20-trione 3,20-diketal is accompfi'shed by mixing said diketal with areducing 'agent in the presence of an organic solvent which isnon-reactive under the conditions of reaction. Reducing agents such as,for example, lithium aluminum hydride, lithium bo'rohydride, sodiumborohydride, hydrogen in the presence of catalysts such as platinum orRaney nickel and others are operative with lithium aluminum hydridebeing preferred. Solvents such as. for example, ether, benzene,tetrahydrofuran, petrolium ether. and others are satisfactory for thereduction reaction medium. In a preferred embodiment of the reaction,lithium aluminum hydride is admixed with a suitable organic solvent suchas ether, the diketal is dissolved in a solvent such as, for example,benzene, and the admixture is then combined to form the reactionmixture. The temperature of the reaction mixture is usually maintainedbetween about zero and 100 degrees centigrade with a temperature betweenabout room temperature and the reflux temperature of the reactionmixture being preferred, where a reaction period varying from aboutone-half to about eight hours or more, with about two hoursbeingpreferred. The ratio of reducing agent to starting steroid can be variedconsiderably over a wide range, a substantial excess of the reducingagent generally being employed with mole ratios up to fifty to one.

According to the second alternative, i. e., selective' hydrolysis of a3,20-diketal to make the 3-monoketals of'this invention, the process isclaimed in application Serial No. 304.852. previously referred to. Asdisclosed in that application the preferential hydrolysis is highlyunexpected since it is known that ketal groups are comparativelysensitive, and it would be expected under normal conditions that bothketal groups would be hydrolyzed. However, it is possible preferentiallyto remove the 20- ketal group of the starting compound while the 3-ketalgroup remains intact. This is apparently due to'the presence of thea-halo ketal moiety of the ketals which affords greater stability tothat portion of the molecule. The 3,20-diketal starting material isdissolved in an organic solvent and this solution is admixed with atleast a theoretical amount, and preferably an excess, of an acidhydrolyzing agent. The organic solvent can be either of thewater-miscible type, such as, for example, acetone, methanol, ethanol,dioxane, and the like, or the organic solvent can be of thewater-immiscible type such as, for example, ether, benzene, chloroform,hexane, and the like. If the Water-miscible solvent is used, thereaction takes place in a homogeneous system, whereas, if awaiterimmiscible solvent is utilized, the reaction mixture forms atwo-phase heterogeneous systetm which must be stirred in order to bringthe reactants into contact with each other and cause hydrolysis.Ordinarily, it is preferred to use a temperature between about twentyand about forty degrees centigrade in carrying out the reaction, butte1n peratures as low as zero and as high as degrees centigrade or evenhigher are operative. The time required for the reaction is not criticaland can be varied between about one and about 24 hours, the length oftime being dependent on the temperature and the hydrolyzing agentemployed. The amount of hydrolyzing agent employed may be varied over awide range since the acid acts as a catalyst for the reaction. Amountsfrom a trace to large excess of the hydrolyzing agent are operative. Theacid hydrolyzing agent for the process of the present invention is astrong acid such as, for example, sulfuric acid, hydrochloric acid,metaor para-toluenesulfonic acids, naphthalenesulfonic acid,benzenesulfonic acid, orthochlorobenzenesulfonic acid, tri-chloroaceticacid, or the like, with sulfuric acid and hydrochloric acid being thepreferred acids. The acid hydrolyzing agent is generally employed as adilute aqueous solution, and in dilute con centrations. Acidconcentrations in the reaction mixture of about 0.1 percent to abouttwenty percent are preferably employed but lower and higherconcentrations are operative. Under these reaction conditions the a-haloketal group is stable and remains unaffected While hydrolysis of theZO-ketal takes place.

When hydrolysis is substantially complete, the product is isolated byconventional procedure, for example, when the resulting mixture iscomposed of an organic layer and a water layer, the organic layer isseparated, the water layer is extracted with ether, and the organicsolutions are combined. The combined extracts are then washed with waterand dried using a drying agent such as anhydrous sodium sulfate.Filtration to remove the drying agent and distillation to remove thesolvent gives the isolated product, which maybe crystallized from any ofthe comrrion organic solvents. Alternatively, the product can beisolated by diluting the reaction mixture with water untilcrystallization of the product takes place. If desired, chromatographicpurification can be employed.

The 4 halo 17a hydroxy ll oxygen substituted pregnane-3,20-dione3-ketals of this invention, aside from being useful as intermediates inthe preparation of Kendall's compound E and compound F and the Zl-estersthereof, are likewise useful as convenient derivatives of thesepharmaccutically active adrenal cortical hormone compounds for purposessuch as purification, storage, isolation from reaction mixtures and thelike.

The foilowing examples are illustrative of the process and products ofthe present invention, but are not to be construed as limiting.

PREPARATION A solution of 25 grams of 3a,l7a-dihydroxypregnanell,20-dione [Sarett, J. Am. Chem. Soc, 70, 1454 (1948)] in 380milliliters of tertiary-butyl alcohol was admixed with five millilitersof concentrated hydrochloric acid and twelve milliliters of water, andthereafter cooled to about fifteeu degrees centigrade. Eighteenmilliliters (2.2 molar equivalents) of tertiary-butyl hydrochlorite wasthen added thereto, whereupon the temperature rose to about 26 degreescentigradc. The reaction mixture was stirred for 4.5 hours although theiodometric titration of an aliquot sample taken from the reactionmixture after two hours showed the reaction to be essentially complete.The volatile components of the reaction mixture were removed bydistillation at reduced pressure leaving a 24.59 gram residue (a yieldof 90.6 prccent of the theoretical, corrected *for the samples takenfrom the reaction mixture for iodometric titrations) of4-chloro-l7a-hydroxypregnane-ilLZO-trione, melting without purificationat 2.20-to- 225 degrees centigrade and having an [111 of plus 91 degrees(acetone).

aromas The corresponding 4-bromo compound is prepared according to theprocedure of Kritchevsky et al. [1. Am. Chem. Soc., 74, 483 (1952)].

PREPARATION 2.-4 CHLORO 17 rrmaoxxrnnomma- 3,11,20-11uoun 3,20-ETHYLBNBGLYCOL DIKETAL A solution of five grams of4-chloro-17a-hydroxypregname-3,11,20-trione (from Preparation 1), tenmilliliters of ethylene glycol, 0.30 gram of para-toluenesulfonic acidmonohydrate and 500 milliliters of benzene was placed in a reactionflask which was equipped with a reflux condenser and a water trap soarranged that the condensed vapors passed through the water trap beforereturning to the reaction flask. The mixture was heated to reflux andwas allowed to reflux for six hours while at the same time beingagitated. The water which formed was removed by co-distillation withbenzene and was collected in the water trap. The reaction mixture wascooled, washed with a dilute solution of sodium bicarbonate and withwater, and then dried and concentrated to dryness under reducedpressure. The white crystalline residue was dissolved in 85 millilitersof ethyl acetate and the solution was cooled until crystallization tookplace. The crystalline 4-chloro 17oz hydroxypregnane-3,11,20-trione3,20- ethylene glycol diketal was isolated by filtration and weighed1.986 grams; melting point 232 to 236 degrees centigrade. A second cropof 1.928 grams, melting point 232 to 235 degrees centigrade, wasobtained by concentration of the mother liquor. The two crops werecombined and recrystallized from methylene chloride-hexane, benzene, andethyl acetate, in that order, to yield purified product of melting point239 to 242 degrees centigrade; [111 plus 55 degrees (acetone).

Analysis-Calculated for CzsI-Ia-zOaCl: C, 64.02; H, 7.95; Cl, 7.56.Found: C, 64.57; H, 7.86; Cl, 7.55.

PREPARATION 3.4 CHLORO 115,170: onryouoxvrnnomun-3,20-nronn3,20-ETHYLENE GLYCOL DIKETAL To a solution of thirteen grams of lithiumaluminum hydride in one liter of anhydrous ether was added, withstirring, a solution of 13.79 grams of4-chloro-17a-hydroxypregnane-3,l1,20-trione 3,20-ethylene glycol diketal(from Preparation 2) in 200 milliliters of benzene. The reaction mixturewas stirred at room temperature for one hour and was then heated atreflux for an additional hour. After cooling, the mixture was hydrolyzedby the cantious addition of a solution of 100 milliliters ofhydrochloric acid in 150 milliliters of water. Stirring at roomtemperature was continued for several hours, after which the organiclayer was separated and the water layer was extracted with methylenechloride. The methylene chloride extract was combined with the organiclayer and the whole was washed with water and dilute sodium bicarbonatesolution, dried and evaporated to dryness. The residue was trituratedwith ether and yielded 8.38 grams of4-chloro-115,17a-dihydroxypregnane-3,ZO-dione 3,20- ethylene glycoldiketal; melting point 212 to 218 degrees centigrade. An additional 1.51grams was obtained from the mother liquor. Several recrystallizationsfrom a mixture of ethyl acetate-hexane gave purified material melting at222 to 224 degrees centigrade.

Analysis.Calculated for CzsHasOeCl: C, 63.74; H, 8.35; Cl, 7.53. Found:C, 63.80; H, 8.30; Cl, 7.35.

Example 1.-4-chlor0-1 15,1 7a-dihydr0xypregnane- 3,20-di0ne 3-ethyleneglycol ketal A solution of one gram of4-chloro-11B,l7a-dihydroxypregnane-3,20-dione 3,20-ethylene glycoldiketal (from Preparation 3) in fifty milliliters of acetone containingten milliliters of water and 0.1 milliliter of sulfuric acid waspermitted to stand at room temperature for two hours. The solution wasthen concentrated under a stream of air, diluted with water, andextracted with ethylene dichloride. The ethylene dichloride extract,after drying, was chromatographed over eighty grams of .6 Florisil(magnesium silicate). The chromatograph was eluted witheighty-milliliter fractions of solvent as indicated below.

Residue Fraction No. Solvent (Weight,

l-B ethylene dichloride 5 t ethyene dichloride plus 4% acetone Fractions4-8 (708 milligrams) were combined and recrystallized from ethylacetate-hexane to give 569 milligrams of4-chloro-llfl,l7a-dihydroxypregnane,3,20-dione 3-ethylene glycol ketal;melting point 183 to 185 degrees centigrade. Further recrystallizationfrom ethyl acetatehexane resulted in purer product of melting point 194to 196 degrees centigrade (with decomposition); [otIl plus 82 degrees(acetone).

Analysis.Calculated for CzaHsaOsCl: C, 64.70; H, 8.26. Found: C, 64.57;H, 8.13.

Example 2.--4-chloro-21-bramo-11fi,1 7a-dihydr0xypregnane-3,20-dione3-ethylene glycol ketal Four hundred milligrams of4-chloro-11p,17a-dihydroxypregnane-3,20-dione 3 ethylene glycol ketal(from Example 1) was dissolved in fifteen milliliters of chloroform anda total of 3.2 milliliters of bromine in acetic acid was added dropwiseand at such a rate as to permit decolorization of each drop before thesubsequent drop was added. The solution was then diluted with ether,washed with a cold dilute solution of sodium bicarbonate, and withwater, and dried. Removal of the solvent gave 320 milligrams of4'chloro-21-bromo-l1)S,17a-dihydroxypregnane-3,20-dione 3-ethyleneglycol ketal; melting point 199 to 201 degrees centigrade (withdecomposition). Infrared analysis confirmed the structure proposed.

Analysis.-Calculated for C23H3505B1'Cl: Total halogen, 22.76. Found:Total halogen, 21.75.

The corresponding 4-bromo compound is prepared from4-bromo-11p,17a-dihydroxypregnane-3,20-dione 3- ethylene glycol ketal byfollowing the procedure of the above example.

Example 3.--4-chl0ro-I119,17a-dihydr0xy-21-acetoxypregnane-3,20-dione3-ethylene glycol ketal A mixture of 1.77 grams (0.0035 mole) of4-chlorol 1B,17at-dihydroxy-2l-bromopregnane3,20-dione 3-ethylene glycolketal (from Example 2), two grams of potassium acetate, fifty milligramsof potassium iodide, and 0.5 milliliter of acetic acid in 300milliliters of acetone was heated under reflux for sixteen hours. Themixture was filtered and the filtrate was concentrated to dryness underreduced pressure. The residue was dissolved in ethyl acetate, filteredto remove inorganic salts, and was allowed to crystallize. The yield of4-chloro-11fl,l7adihydroxy 21 acetoxyprengane 3,20 dione 3 ethyleneglycol ketal was 1.39 grams (84.8 percent); melting point 231 to 234degrees centigrade. Recrystallization from the same solvent raised themelting point to 232 to 233 degrees centigrade.

Analysis.-Calculated for CasHsrOrCl: C, 61.91; H, 7.69; Cl, 7.31. Found:C, 62.17; H, 7.73; Cl, 7.16.

Following the same procedure as above, other acyloxy groups may besubstituted in the 21-position by reaction of 4 chloro2l-bromo-11fl,l7a-dihydroxypregnane- 3,20-dione B-ethylene glycol ketalwith the appropriate acylating agent. Such acyloxy groups includepropionoyloxy, butyroyloxy, valeroyloxy, hexanoyloxy, hep- 7 tanoyloxy,octanoyloiey, benzoyloxy, and others. The preferred acylo'ny' groups arethose derived from a hydrocarbon monocarboxylic acid containing from oneto eight carbon atoms, inclusive.

In addition, the corresponding 4-bromo compounds are similarly preparedfrom 4-bromo-1 15,17a-dihydroxy- 2l-bromopregnane-3,20-dione 3-ethyleneglycol ketal according to the procedure of the above example.

Example 4. 4 -chlr0-1 I 5,] 7 a,21 -trihydroxypregnane- 3,20-a'i0ne3-ethylene glycol ketal A solution of 100 milligrams of4-Chl0lO-11]3,17udihydroxy-Z l -bromopregnane-3,20-dione 3-ethylcneglycol ketal (from Example 2) in fifty milliliters of alcohol and fiftymilliliters of 0.1 N sodium hydroxide was permitted to stand at 25degrees centigrade under nitrogen for ten minutes. The pH was adjustedto seven with dilute hydrochloric acid and the solution was then dilutedwith 200 milliliters of water and repeatedly extracted with ether.Theether extract was evaporated to dryness and the residue was purifiedby chromatography overFlorisil to yield ten milligrams of 4-chlorollfl',l7a,2l trihydroxypregn ane 3,20 dione 3 ethyleneglycol ketal. Thestructure of this compound, which was not crystalline, was confirmed byinfrared analysis.

The corresponding 4-bromo compound is prepared from 4 bromo 115,170dihydroxy 21 bromopregnane-3,20-dione 3-ethylene glycol ketal byfollowing the procedure of the above example.

5 4-chloro-17a-hydr0xypregnane-3J1,20-

trione 3-ethylene glycol ketal Example Example 6.4-chl0r0-2I-br0mo-17a-hydroxypregnane- 3,11,20-trfrme 3-cllzylene glycollrelul Following the procedure of Example 2,4-chloro-l7ahydroxypregnane-ILI1,20-trione B-ethylene glycol ketal ofExample 5 is dissolved in chloroform and brominated with bromine toproduce 4-chloro-2l-bromo-l7a-hydroxypregnanc-3,ll,20 trione 3-ethylenoglycol ketal.

Example 7.4-chl0r0-1 7a-hy1Ir0xy-2I -acetoxypregnane 3,11,20-tri0ne3-ethylene glycol ketal Following the procedure of Example 3,4-chloro-l7ahydroxy 2l bromopregnane 3,11,20 trione 3 ethylene glycolketal of Example 6 is treated with potassium acetate, potassium iodideand a small amount of acetic acid to produce4-chloro-l'la-hydroxy-2l-acetoxypregnane-3, l 1,20-trione 3 ethylcneglycol ketal.

E xrmzple 8.-4-chloro-2l-acet0xy-17a-hydroxypregnand 3,11,20-trr'one3-ethylene glycol ketal A mixture of 500 milligrams of4-chloro-2l-acetoxyl7a-hydroxyprcgnane-3J1,20-trione is mixed with twomilliliters of ethylene glycol, about fifty milligrams ofparatoluenesulfonic acid and 100 milliliters of benzene. The mixture wasstirred and heated under reflux for seventeen hours. The water formed inthe reaction was co-distilled with the benzene. The benzene solution waswashed with sodium bicarbonate, dried and concentrated. Crystallizationfrom 2-propanol gave 150 milligrams (25 percent yield) of white crystalsof 4-chloro-2lacetoxy 17a hydroxypregnane 3,11,20 trione 3 ethyleneglycol ketal. The crystals had a melting point of 207 to 212 degreesCentigrade with decomposition. Further crystallization from the samesolvent raised the melting point to 228-232 degrees centigrade. Infrareddata confirmed the structure of4-chloro-2l-acetoxy-17ahydroxypregnane-3,1 1,20?tri0ne 3-kctal.

Analysis.Calculated for CzaHnOaCl: C, 62.93; H,

ti I) 8 7.1 2; G1, 8.68. Found: C, 61.99, 62.36; H, 7.57, 7.48; Cl',7.60, 7.56;

9. 4-chl0ro-2l-acetoxy-]113,17a-dihydroxypregnanedjli dione '3-ketalFollowing the procedure of Example 8, 4-chloro-21-acetoxy-l1p,17wdihydroxypregnane-3,ZO-dione is reacted with ethyleneglycol in a benzene reaction mixture containing a small amount ofpara-toluencsulfonic acid to produce 4-chloro-2l-acotoxy-1 1B, 17a-dihydroxypregnane- 3,20-dione 3-ketal.

In the same manner as given in Examples 1 to 5, in elusive, startingwith the appropriate 3,20-diketal, other steroid 4-halo-3-monoketals areprepared including 4 brorno l'lfl,l7a,2l trihydroxypregnane 3,20-dione3-ethylene glycol ketal,4-chloro-17a-hydroxy-21-acetoxypregnane-3,ll,2l)-trione3-butane-l,3-diol ketal,4-chlorol1.;8,17a,2l-trihydroxypregnaneSJO-dione 3-hexane-l,2- dioimonoketal, 4 bromo-lla,l7a-dihydroxy 2l-acctoxypregnane-3,20 dione3-propane-l,2-diol monoketal and the like.

As stated in the foregoing, the compounds of the present invention areuseful in the preparation of physiologically active hormones such as,for example, Kendalls compound F and acylates thereof.

Compound F acylates are prepared by first treating a 4 halo 11,6,17adihydroxy 21 acyloxyprcgnane- 3,20-dione 3*monoketal (Example 3) with anacid in the presence of a nitrogen carbonyl reagent such, as forexample, semicarbazide, hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, hydroxylamine, and the like, to cause in asingle step (1) removal of the kctal group, (2) formation of a ketonicnitrogen derivative at the 3-position, and (3) dehydrohalogenation atthe 4 (5)- position; The 4(5)-unsaturated ketonic nitrogen deriva tivethus-formed, with or without isolation, is then reacted with an exchangereagent capable of entering into an exchange reaction to form a ketonicnitrogen derivative of the exchange reagent and free the 3-keto group ofthe steroid and yield compound F acylate. Representative exchangereagents are pyruvic acid, 2-ketogluconic acid, glucuronic acid,para-hydroxybenzaldehyde, orthohydroxybenzaldehyde, salicylaldchyde,ethylacetoacetate, and the like. Similarly, free compound F is preparedfrom a 4-halo-l1p,l7a,2l-trihydroxypregnane-3,20-dione 3-monokctal bytreatment with an acid in the presenceof nitrogen carbonyl reagent,followed by reaction with a ketonic nitrogen derivative exchangereagent.

Example Example A .--Kendall's compound F acetate A solution of 440milligrams of 2,4-dinitrophenylhydrazine in three milliliters of aceticacid and three milliliters of water containing 0.2 milliliter ofsulfuric acid was prepared by warming the ingredients to about seventyto eighty degrees centigrade. This solution was added to a suspension of4-chloro-ll;8,l7a-dihydroxy-2l-acetoxypregnane-3,20-dione 3-ethyleneglycol ketal in five milliliters of acetic acid and in the presence ofan atmosphere of nitrogen which was maintained throughout the reaction.The mixture was heated at seventy degrees centigrade for 0.5 hour andwas then permitted to stand at room tempcraurre for' two hours. Redneedles of unsaturated hydrazone crystallized on standing and wereredissolved by the addition of ten milliliters of acetic acid and tenmilliliters of chloroform. One milliliter of pyruvic acid was added andthe reaction mixture heated at fifty degrees centigrade for two hours,after which, two grams of sodium acetate was added and the solutionstirred for five minutes. After removal of the solvent under reducedpressure, the

residue was triturated three times with chloroform and filtered toremove the insoluble sodium salt of the 2,4- dinitrophenylhydrazone ofpyruvic acid. The chloroform solution was washed successively withwater, dilute sodium bicarbonate solution, water, and was then driedover sodium sulfate and concentrated to dryness.

For ease of isolation and in order to compensate for any hydrolysis thatmight have occurred during the reaction, the residue was reacetylatedwith a mixture of two milliliters of acetic anhydride and twomilliliters of pyridine at 26 degrees centigrade for one hour. Theexcess acetic anhydride was destroyed by the addition of water and theproduct was extracted with methylene dichloride. The methylenedichloride solution was washed successively with dilute hydrochloricacid, water, dilute sodium bicarbonate solution, water, and was thendried over sodium sulfate and concentrated to dryness. The residue wascrystallized from acetone and gave, in two crops, 560 milligrams (71.1percent) of crude crystalline compound F acetate. The crude crystallineproduct was recrystallized from fifty milliliters of methanol, aftertreatment with a decolorizing agent (Darco 6-60), to yield 410milligrams (51.8 percent) of purified compound F. acetate; melting point208 to 211 degrees centigrade.

Example B.Kendall's compound F acetate Under an atmosphere of nitrogen,a mixture of one gram of 4-chloro-l 15,17a-dihydroxy2l-acetoxypregnane-3,20-dione 3-ethylene glycol ketal, thirty milliliters of acetic acid,six milliliters of water, and 72 milligrams of semicarbazidehydrochloride were heated at seventy degrees Centigrade for five hours,after which the solvent was removed by distillation under reducedpressure. The residue was partially dissolved in a mixture of water andethyl acetate giving 190 milligrams of insoluble material which wasisolated by filtration. The organic layer was separated, washed, andevaporated to dryness to give 807 milligrams of an oil. Both the solidmaterial and oil were combined and dissolved in a mixture of twentymilliliters of dioxane. five milliliters of water, two milliliters ofpyruvic acid and five drops of acetic acid. This mixture was then heatedat 65 degrees centigrade for 1.5 hours, after which the solvent wasdistilled under reduced pressure and the residue was dissolved inmethylene dichloride. After washing and drying, the methylene dichloridesolution was evaporated to dryness and the residue was reacetylatcd witha mixture of three milliliters of pyridine and two milliliters of aceticanhydride. The reacetylated material was worked up as in Example A togive 680 milligrams of crude crystalline compound F acetate.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. 4 halo 17a,21 dihydroxy-ll-oxygen-substitutedpregnane-3,20-dione3-alkylene glycol monoketals and 21- esters thereof having the followinggeneral formula:

CHQR' ---OH RI! (CH1) nO wherein X is a halogen selected from the groupconsisting of chlorine and bromine, R is selected from hydrogen andlower-alkyl groups, n is an integer from one to two, inclusive, R isselected from hydroxy and acyloxy groups, the acyl radical radical ofwhich is that of a hydrocarbon monocarboxylic acid containing from oneto eight carbon atoms, inclusive, and R" is selected from a-hydroxy, S-hydroxy and keto groups.

2. 4 chloro 11,8,17a-dihydroXy-2l-acyloxypregnane- 3,20-dione S-alkyleneglycol monoketals in which the acyl radical is that of a hydrocarbonmonocarboxylic acid containing from one to eight carbon atoms,inclusive.

3. 4 chloro-l1B,17a,21-trihydroxypregnane-3,ZO-dione 3-alkylene glycolmonoketals.

4. 4 chloro-l7a-hydroxy-2l-acyloXypregnane-3,l1,20- trione 3-alkyleneglycol monoketals in which the acyl radical is that of a hydrocarbonmonocarboxylic acid containing from one to eight carbon atoms,inclusive.

5. 4 chloro-l70:,2l-dihydroxypregnane-ZlJ1,20-trione 3-alkylene glycolmonoketals.

6. 4 chloro-l 15,l7u-dihydroxy-2l-acetoxypregnane- 3,20-dione 3-ethyleneglycol ketal.

7. 4 chloro-l 118,17a,21-trihydroxyprcgnanc-3,Zll-dione S-ethyleneglycol ketal.

8. 4 chloro-17a-hydroxy-21-acetoxypregnane-3,11,20- trione 3-ethyleneglycol ketal.

9. 4 halo -11p ,17u,21-trihydroxypregnane-3,20-dione 3-ethylene glycolmonoketals, wherein the halogen is of atomic weight from 35 to 80, whichmay be represented by the formula:

CH 0 ll wherein R is an ethylene glycol ketal group and X is halogen asdefined above.

No references cited.

1. 4 - HALO - 17A, 21 -DIHYDROXY-11-OXYGEB-SUBSTITUTEDPREGNANE-3,20-DIONE 3-ALKYLENE GLYCOLMONOKETALS AND 21ESTERS THEREOF HAVING THE FOLLOWING GENERAL FORMULA: